Inhibiting autophagy does not decrease drug resistance in breast cancer stem-like cells under hypoxic conditions

Introduction: Breast cancer has been one of the most frequently diagnosed cancers in women over the past decade. The presence of a breast cancer stem cell (BCSC) population within breast tumors significantly contributes to malignancy and drug resistance. Under the hypoxic conditions of breast tumors, BCSCs exhibit increased resistance to chemotherapy, complicating treatment and reducing its efficacy. Consequently, targeting BCSCs is considered a crucial strategy for breast cancer treatment. We hypothesize that the chemotherapy resistance of BCSCs is dependent on the upregulation of autophagy triggered by hypoxia. This study aims to investigate the relationship between autophagy and drug resistance of BCSCs in hypoxic conditions. Methods: BCSCs were isolated from Vietnamese breast cancer cell line 1 (VNBRCA1) based on expression of CD44 and CD24. Cobalt (II) chloride (CoCl2) was used to simulate a hypoxic environment in monolayer cell cultures. The hypoxic status of BCSCs was confirmed by the upregulation of the HIF-1α gene. Autophagy activation was assessed through the expression of autophagy-related genes (LC3B, Beclin-1, AMPK, PI3K, AKT). Drug resistance was evaluated by measuring the expression of ABCC10 and assessing cell proliferation under cisplatin treatment. Results: The study revealed that CoCl2 treatment led to high expression of HIF-1α and significant upregulation of LC3B in BCSCs, together with enhanced expression of ABCC10. Consequently, BCSCs exhibited marked resistance to cisplatin in the hypoxic environment. However, inhibition of autophagy using the autophagy inhibitor 3-methyladenine (3-MA) did not reduce cisplatin resistance in hypoxic conditions. Conclusion: The findings indicate that in hypoxic conditions, BCSCs enhance both the autophagy process and drug resistance. However, the drug resistance of BCSCs in hypoxic conditions is not directly associated with the upregulation of autophagy. Therefore, targeting autophagy inhibition may not be an effective strategy to reduce drug resistance in hypoxia.